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    Clinical Trial Results:
    A phase 1b/2 trial to evaluate the safety of radium-223 dichloride (BAY 88-8223) in combination with bortezomib and dexamethasone in patients with relapsed multiple myeloma

    Summary
    EudraCT number
    		 2016-002438-58
    Trial protocol
    		 ES  
    Global end of trial date
    20 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Feb 2020
    First version publication date
    05 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    18987
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02928029
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser Wilhelm Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Mar 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Mar 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Phase 1b part (open-label) 1. To evaluate the safety of the combination of radium-223 dichloride plus bortezomib and dexamethasone 2. To determine the dose of radium-223 dichloride that will be used in the phase 2 part of the study (maximum tolerated dose [MTD] or recommended phase 2 dose [RP2D]) Phase 2 part (double-blind, randomized): 1. To evaluate the combined complete response (CR) + very good partial response (VGPR), as determined by International Myeloma Working Group (IMWG) uniform response criteria
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Feb 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 4
    Country: Number of subjects enrolled
    United States: 2
    Worldwide total number of subjects
    7
    EEA total number of subjects
    1
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    2
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in 7 study centers, the first patient first visit was on 10/Feb/2017 and last patient last visit on 20/Mar/2019

    Pre-assignment
    Screening details
    		 10 subjects were enrolled in the study; 4 subjects in Cohort 1 and 6 subjects in Cohort 2. 3 of these subjects failed screening procedures, all for the reason “inclusion criteria not met”. No subjects were started in the Phase 2 part of the study prior to study termination

    Period 1
    Period 1 title
    Phase 1b (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Radium-223 dichloride 33 kBq/kg + Bortezomib and Dexamethasone
    Arm description
    		 Subjects received 33 kiloBecquerel (kBq)/kg body weight every 6 weeks for a total of 6 radium-223 dichloride doses in combination with BOR and DEX
    Arm type
    		 Experimental

    Investigational medicinal product name
    Radium RA 223 dichloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    33 kBq/kg body weight, administered approximately 36 weeks: 6 doses; 1 dose every 6 weeks

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.3 mg/m^2/dose, administered on Days 1, 4, 8, and 11 in a 21-day cycle, for 8 cycles. For extended therapy beyond 8 cycles, BOR was administered on Days 1 and 15 of a 28-day cycle for up to 2 years after the first dose of study treatment, or until progression-free survival (PFS) event occurred, the subject withdrew consent or an unacceptable toxicity developed, whichever occurred first.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg, administered on Days 1, 4, 8, and 11 in a 21-day cycle, for 8 cycles. DEX administration may have been split over 2 days (on the day of BOR administration and the day after BOR administration) at the discretion of the Investigator. For extended therapy beyond 8 cycles, DEX was administered orally at 20 mg/dose, on Days 1 and 15 of a 28-day cycle along with BOR for up to 2 years after the first dose of study treatment or until a progression-free survival (PFS) event occurred, the subject withdrew consent or an unacceptable toxicity developed, whichever occurs first

    Arm title
    		 Radium-223 dichloride 55 kBq/kg + Bortezomib and Dexamethasone
    Arm description
    		 Subjects received 55 kBq/kg body weight every 6 weeks for a total of 6 radium-223 dichloride doses in combination with BOR and DEX
    Arm type
    		 Experimental

    Investigational medicinal product name
    Radium RA 223 dichloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    55 kBq/kg body weight, administered approximately 36 weeks: 6 doses; 1 dose every 6 weeks

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.3 mg/m^2/dose, administered on Days 1, 4, 8, and 11 in a 21-day cycle, for 8 cycles. For extended therapy beyond 8 cycles, BOR was administered on Days 1 and 15 of a 28-day cycle for up to 2 years after the first dose of study treatment, or until progression-free survival (PFS) event occurred, the subject withdrew consent or an unacceptable toxicity developed, whichever occurred first.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg, administered on Days 1, 4, 8, and 11 in a 21-day cycle, for 8 cycles. DEX administration may have been split over 2 days (on the day of BOR administration and the day after BOR administration) at the discretion of the Investigator. For extended therapy beyond 8 cycles, DEX was administered orally at 20 mg/dose, on Days 1 and 15 of a 28-day cycle along with BOR for up to 2 years after the first dose of study treatment or until a progression-free survival (PFS) event occurred, the subject withdrew consent or an unacceptable toxicity developed, whichever occurs first

    Number of subjects in period 1
    		Radium-223 dichloride 33 kBq/kg + Bortezomib and Dexamethasone Radium-223 dichloride 55 kBq/kg + Bortezomib and Dexamethasone
    Started
    3
    4
    Completed
    0
    0
    Not completed
    3
    4
         Clinical progression
    1
    2
         Radiological progression
    1
    -
         AE not related to clinical progression
    1
    1
         Withdrawal by Subject
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Radium-223 dichloride 33 kBq/kg + Bortezomib and Dexamethasone
    Reporting group description
    		 Subjects received 33 kiloBecquerel (kBq)/kg body weight every 6 weeks for a total of 6 radium-223 dichloride doses in combination with BOR and DEX

    Reporting group title
    Radium-223 dichloride 55 kBq/kg + Bortezomib and Dexamethasone
    Reporting group description
    		 Subjects received 55 kBq/kg body weight every 6 weeks for a total of 6 radium-223 dichloride doses in combination with BOR and DEX

    Reporting group values
    		 Radium-223 dichloride 33 kBq/kg + Bortezomib and Dexamethasone Radium-223 dichloride 55 kBq/kg + Bortezomib and Dexamethasone Total
    Number of subjects
    		 3 4 7
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 1 1 2
        Elderly (from 65-84 years)
    		 2 3 5
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.0 ± 5.0 68.3 ± 10.3 -
    Gender Categorical
    Units: Subjects
        Female
    		 1 2 3
        Male
    		 2 2 4
    Race
    Units: Subjects
        White
    		 0 2 2
        Asian
    		 2 2 4
        Multiple
    		 1 0 1
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 3 3 6
        Hispanic or Latino
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Radium-223 dichloride 33 kBq/kg + Bortezomib and Dexamethasone
    Reporting group description
    		 Subjects received 33 kiloBecquerel (kBq)/kg body weight every 6 weeks for a total of 6 radium-223 dichloride doses in combination with BOR and DEX

    Reporting group title
    Radium-223 dichloride 55 kBq/kg + Bortezomib and Dexamethasone
    Reporting group description
    		 Subjects received 55 kBq/kg body weight every 6 weeks for a total of 6 radium-223 dichloride doses in combination with BOR and DEX

    Subject analysis set title
    SAF
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set consists of all subjects who received at least one administration of study treatment

    Primary: Phase1: MTD/RP2D determined by the incidence of DLTs

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    End point title
    		 Phase1: MTD/RP2D determined by the incidence of DLTs [1]
    End point description
    Maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) determined by incidence of dose limiting toxicity (DLT) using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 for the severity grade
    End point type
    Primary
    End point timeframe
    From the start of study medication through 3 weeks after administration of the second dose of radium-223 dichloride
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: MTD/RP2D was not determined in this study
    End point values
    		 Radium-223 dichloride 33 kBq/kg + Bortezomib and Dexamethasone Radium-223 dichloride 55 kBq/kg + Bortezomib and Dexamethasone
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: KBq/kg
        number (not applicable)
    Notes
    [2] - This study was stopped prior to the MTD being defined. Accordingly, there was no RP2D determined
    [3] - This study was stopped prior to the MTD being defined. Accordingly, there was no RP2D determined
    No statistical analyses for this end point

    Primary: Phase 1: The number of subjects with treatment-emergent adverse events (TEAEs), drug-related TEAEs, and treatment-emergent serious AE

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    End point title
    		 Phase 1: The number of subjects with treatment-emergent adverse events (TEAEs), drug-related TEAEs, and treatment-emergent serious AE [4]
    End point description
    A treatment-emergent adverse event (TEAE) is defined as any event arising or worsening after start of study drug administration until the end of the treatment period
    End point type
    Primary
    End point timeframe
    From the start of study medication up to 30 days after the last dose of study medication
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis for this end-point is descriptive
    End point values
    		 Radium-223 dichloride 33 kBq/kg + Bortezomib and Dexamethasone Radium-223 dichloride 55 kBq/kg + Bortezomib and Dexamethasone
    Number of subjects analysed
    3
    4
    Units: subjects
        Any TEAE
    3
    4
        Any drug-related TEAE
    3
    4
        Any treatment-emergent serious AE
    2
    1
    No statistical analyses for this end point

    Secondary: Phase 1: The number of subjects with complete response (CR) and very good partial response (VGPR)

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    End point title
    		 Phase 1: The number of subjects with complete response (CR) and very good partial response (VGPR)
    End point description
    Determined by International Myeloma Working Group (IMWG) uniform response criteria. CR: Negative immunofixation of serum and urine, disappearance of any soft-tissue plasmacytomas, and <5% plasma cells in bone marrow; in patients for whom only measurable disease is by serum free light chain (FLC) level, normal FLC ratio of 0.26 to 1.65 in addition to CR criteria is required; 2 consecutive assessments are needed. VGPR: Serum and urine M-component detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-component plus urine M-component <100 mg/24 hours (hrs); in patients for whom only measurable disease is by serum FLC level, >90% decrease in difference between involved and uninvolved FLC levels, in addition to VGPR criteria, is required; 2 consecutive assessments are needed
    End point type
    Secondary
    End point timeframe
    Up to 2 years after last dose of study medication
    End point values
    		 Radium-223 dichloride 33 kBq/kg + Bortezomib and Dexamethasone Radium-223 dichloride 55 kBq/kg + Bortezomib and Dexamethasone
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: subjects
    Notes
    [5] - Subjects were not evaluable per International Myeloma Working Group (IMWG) uniform response criteria
    [6] - Subjects were not evaluable per International Myeloma Working Group (IMWG) uniform response criteria
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the start of study medication up to 30 days after the last dose of study medication
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Radium-223 33 kBq/kg + BOR/DEX
    Reporting group description
    		 Subjects received 33 kiloBecquerel (kBq)/kg body weight every 6 weeks for a total of 6 radium-223dichloride doses in combination with BOR and DEX

    Reporting group title
    Radium-223 55 kBq/kg + BOR/DEX
    Reporting group description
    		 Subjects received 55 kBq/kg body weight every 6 weeks for a total of 6 radium-223dichloride doses in combination with BOR and DEX

    Serious adverse events
    		 Radium-223 33 kBq/kg + BOR/DEX Radium-223 55 kBq/kg + BOR/DEX
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 4 (25.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Radium-223 33 kBq/kg + BOR/DEX Radium-223 55 kBq/kg + BOR/DEX
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    4 / 4 (100.00%)
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 4 (50.00%)
         occurrences all number
    4
    2
    Chest pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Chills
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Face oedema
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    1
    2
    Injection site reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Dyspnoea
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Hiccups
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Nasal congestion
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Throat irritation
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Productive cough
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Psychiatric disorders
    Hallucination
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 4 (75.00%)
         occurrences all number
    0
    3
    Investigations
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    18
    Platelet count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    16
    Weight decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Tremor
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Presyncope
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Anaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Neutropenia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    11
    Eye disorders
    Eye discharge
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Eyelid oedema
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Periorbital oedema
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Visual acuity reduced
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    2
    Constipation
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 4 (75.00%)
         occurrences all number
    2
    3
    Abdominal pain upper
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 4 (75.00%)
         occurrences all number
    2
    3
    Nausea
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Dry mouth
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Skin exfoliation
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Nocturia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    Infections and infestations
    Cystitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Influenza
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Rhinovirus infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Septic arthritis streptobacillus
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Aug 2017
    • Due to changes in the therapies of choice for MM patients, daratumumab cohorts (Cohorts 3 and 4) were added to the study with significant changes to the study design introduced throughout the protocol to accommodate the new background treatment. • Radium-223 dichloride dose level of 88kBq/kg body weight was removed from the study. • The randomized phase 2 part of the study has been removed.
    18 May 2018
    • Due to feedback on the new study design presented in protocol amendment 1 received from some authorities and investigators, the daratumumab cohort was removed from the study. Consequently, the study protocol was revised to return to the original backbone treatment with only bortezomib/dexamethasone with a randomized expansion cohort in order to obtain more robust data on the anti-multiple myeloma activity of radium-223 dichloride in combination with bortezomib/dexamethasone. • Added the randomized phase 2 part of the study to all applicable sections, including phase 2 study objectives and randomization steps. • Clarifications were added related to MM and bone biomarker exploratory endpoints. • Added clarifications to the safety follow up for the collection of bone fracture and bone associated events and clarification added for the recommended use of bone health agents.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    As no subject entered phase 2, endpoints for this phase could not be listed due to system limitation
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